Abstract

Skin aging and its clinical manifestation is associated with altered molecular metabolism in the extracellular matrix of the dermis. In a pilot open-label study, we investigated the effect of a dietary supplement, BioCell Collagen® (BCC), which contains a naturally occurring matrix of hydrolyzed collagen type II and low-molecular-weight hyaluronic acid and chondroitin sulfate, in 26 healthy females who displayed visible signs of natural and photoaging in the face. Daily supplementation with 1 g of BCC for 12 weeks led to a significant reduction of skin dryness/scaling (76%, P = 0.002) and global lines/wrinkles (13.2%, P = 0.028) as measured by visual/tactile score. Additionally, a significant increase in the content of hemoglobin (17.7%, P = 0.018) and collagen (6.3%, P = 0.002) in the skin dermis was observed after 6 weeks of supplementation. At the end of the study, the increase in hemoglobin remained significant (15%, P = 0.008), while the increase in collagen content was maintained, but the difference from baseline was not significant (3.5%, P = 0.134). This study provides preliminary data suggesting that dietary supplementation with BCC elicits several physiological events which can be harnessed to counteract natural photoaging processes to reduce visible aging signs in the human face. A controlled study is necessary to verify these observations.

Introduction

In the human body, the skin is the largest organ and is involved in various functions, including sensation of temperature and pressure and protection from external insults such as pathogens and injury. The epidermis of the skin is composed of stratified squamous epithelium consisting of proliferating basal and differentiated keratinocytes. The dermis is composed of connective tissue consisting of diverse extracellular matrix (ECM) components, including collagen and elastin fibers and glycosaminoglycans (GAGs), which are synthesized by dermal fibroblasts.1

The structural integrity of the dermis is vital for the normal function and youthful appearance of the skin, as this layer lends structural support for the epidermis as well as for the vasculature and appendages of the skin. The structure of the dermis is defined by the ECM, which is primarily composed of type I collagen fibrils, making up 70% to 80% of the dry weight of the skin.2 GAGs in the skin are primarily composed of hyaluronic acid (HA) and dermatan sulfate (DS), and embedded as a ground substance into the collagen fiber network. HA can retain a large number of water molecules, creating turgidity to resist external pressure, while DS proteoglycans such as decorin are involved in interconnecting collagen fibrils to transmit force.3

The skin undergoes natural (chronological) aging, which occurs concurrently with the photoaging process in exposed areas such as the face and arms. Skin changes associated with natural aging are generally characterized by fine wrinkling and laxity, which can be worsened by chronic ultraviolet (UV) light exposure.4 Clinical signs of photoaging include dryness, deep furrows, irregular pigmentation, elastosis, and a leathery appearance.4 The face is a site at which these changes are prominent.

Key molecular and histochemical features underlying age-dependent phenotypic alterations of the human skin include decreased collagen production in dermal fibroblasts, leading to the fragmentation and disarray of collagen fibrils in the dermis.5,6 This structural disturbance results in various physiological consequences, including interference with the mechanical properties of skin and impairment of resident cell functions in the dermis, resulting in disruption of the normal interactions of cells with the ECM microenvironment. 7 Additionally, both natural and photoaging processes appear to cause an imbalance between HA synthases and hyaluronidases, decreasing the integrity and amount of HA.8,9 Eventually, a cycle between defective stimulation of senescent dermal fibroblasts and deterioration of the dermal ECM occurs in association with elevated oxidative stress and heightened activity of ECM-degrading enzymes such as hyaluronidase and matrix metalloproteinases (MMPs), including MMP-1, to perpetuate skin aging.10

There is growing interest in hydrolyzed collagen (or collagen hydrolysate) as a nutraceutical and nutricosmetical solution to these issues because collagen-derived peptides harbor a variety of interesting biological properties implicated in various health benefits. First, hydrolyzed collagen derived from both bovine collagen type I or chicken sternal cartilage collagen type II was shown to stimulate chondrocytes in vitro to produce type II collagen and proteoglycans.11 Second, ingestion of hydrolysates derived from chicken sternal cartilage or porcine skin led to the appearance of various di- and tri-peptides in human serum, with the proline-hydroxyproline (Pro-Hyp) dipeptide as the major form.12 Dipeptide-stimulated human dermal fibroblasts and chondrocytes in vitro synthesize HA, which is responsible for holding water molecules in the skin and making up the synovial fluid in the synovial joint.13 Third, studies involving animal models suggest that ingestion of hydrolyzed collagen enhances the number of fibroblasts together with the density and thickness of collagen fibrils, protecting mice against UV-induced damage in the skin such as epidermal hypertrophy, dermal dehydration, and loss of type I collagen.14,15

Derived from the chicken sternal articular cartilage, BioCell Collagen® (BCC; BioCell Technology, LLC Newport Beach, CA) is a dietary supplement containing a soluble, naturally occurring matrix of hydrolyzed collagen type II and low-molecular-weight HA and chondroitin sulfate. To investigate its effect on skin aging, a pilot open-label study was conducted in 26 females who had undergone natural and photoaging processess in their faces. Daily BCC supplementation for 12 weeks enhanced microcirculation in the dermis, while reducing visible age-dependent signs such as wrinkles in the face.

All the subjects were instructed to take two capsules (1 g) daily in two equally divided doses, one capsule in the morning and one in the evening. This dose was considered to be safe, as a 2-g dose of BCC had been shown to be well-tolerated without associated adverse events in osteoarthritic patients enrolled in a previous clinical trial.16

Results

Basic demographics and facial skin features

Demographics of the 26 subjects who completed the study are summarized in Table 2. Their ages spanned from 35 to 59 years, with an average of 50.65, and most were Caucasian (57.7%), followed by African American (23.1%) and Hispanic (15.4%). All subjects had mild-to-moderate photo-damaged skin and mild-to-moderate fine lines and wrinkles in the crow’s feet region of the left eye as manifested by the scores of 1-6 centimeters on 0-10 cm VAS scoring.

Reduction of global facial lines and wrinkles

Skin aging in the face culminates with the appearance of visible signs such as wrinkles and lines. Measurement of these aging signs using visual/tactile scores showed that 12 weeks of supplementation with BCC led to significant improvement of facial lines and wrinkles with an average reduction of 13.2% (P = 0.028) from baseline (Table 3). An initial increase was noted at week 6 (22.4%, P < 0.001). Another facial aging sign, crow’s feet, displayed a similar trend with a significant increase during the first 6-week period (50.7%), followed by a significant decrease (âˆ’30.4%) in visible aging signs between weeks 6 and 12. Unlike facial lines and wrinkles, however, crow’s feet were not affected significantly by the end of study compared to the baseline level.

Reduction of skin dryness/scaling

Facial dryness and scaling may be associated with the water content in the skin and the skin aging process. Skin dryness or scaling was measured using visual/tactile scores; its mean value at week 12 decreased significantly by 76% (P = 0.002) from the baseline level (Table 3), suggesting that BCC ingestion reduces skin dryness and scaling.

To observe the effect of BCC on skin hydration level, a NOVA meter was used to compare water content of the stratum corneum before and after BCC consumption. Table 4 shows that water content increased by 8% at week 12, although this value was not significant (P = 0.210). Similarly to facial aging signs shown in Table 3, hydration level during the first 6 weeks decreased by 5.4%, but this value was not significant (P = 0.420). A significant increase of 12.5% (P = 0.003, data not shown) occurred between weeks 6 and 12.

Effects of BioCell Collagen ingestion on epidermal and dermal components

Enhancement of hemoglobin content

The Cosmetrics™ SIAscope was used to measure hemoglobin content in the dermis to investigate how microvascular blood circulation is affected by daily ingestion of BCC. The amount of hemoglobin significantly increased by 17.7% (P = 0.018) by week 6 and by 15.0% (P = 0.008) by week 12 (Table 4), suggesting that intake of BCC enhances dermal microcirculation in the face.

The SIAscope was also used to evaluate how the metabolism of key molecules in the skin such as collagen and melanin are affected by BCC supplementation. Table 4 shows that dermal collagen content significantly increased by 6.36% (P = 0.002) by week 6 from baseline, but the 3.45% increase by week 12 was not significant (P = 0.134). Melanin content was not affected significantly.

Adverse events

During the 12-week study period, no adverse eventswere reported, suggesting that daily ingestion of 1 g of BCC was well-tolerated by the subjects (data not shown).

Discussion

Skin aging in the face involves physiological changes in the underlying tissues and is manifested as visible signs such as dryness, laxity, and wrinkles. The results from this study enrolling women who had undergone both natural and photoaging showed that daily supplementation with BCC counteracts some of these changes, as their facial skin presented with fewer visible aging signs.

Daily ingestion of BCC for 12 weeks led to a significant decrease in facial lines and wrinkles as well as in skin dryness and scaling. Improvement of these visible aging signs appears to be correlated with physiological changes in the metabolism of molecules comprising the epidermal and dermal tissues. First, the amount of hemoglobin was elevated in the dermis, implying that blood circulation through the microvasculature in the facial skin improved. As blood carries oxygen, nutrients, and growth factors to the tissue while removing metabolic wastes, improved microcirculation may lead to enhanced homeostasis of the skin. For example, efficient delivery of oxygen and nutrients to the dermis can nourish resident cells, including the dermal fibroblasts, while the structure of dermal ECM may resist various stresses caused by the oxidative aging process.

During the first 6 weeks, there was a significant increase in global fine lines and wrinkles. The cause of this initial worsening of facial aging signs was not clear. Potential factors involved include the physiology (eg, menstruation cycle) of the subjects, seasonal change, or other confounding factors. A placebo-controlled clinical trial is required to exclude these factors in revealing the true effect of BCC.

Second, a significant decrease in skin scaling and dryness appeared to be accompanied by an increase in the water content of the stratum corneum by 8.0% at week 12 from baseline values. However, this increase in hydration level was not significant, suggesting that multiple factors contribute to skin scaling and dryness. Interestingly, although the retention of water molecules in skin tissues is primarily mediated by HA, there is evidence that collagen fibrils may help hydrate the skin, as intake of hydrolyzed collagen protected mice against dermal dehydration.15 It can be speculated that improved health of the epidermis may be due to the effect of daily use of Camay soap. Camay bar soap is primarily used in clinical studies for subject compliance reasons, as it properly cleanses the skin without over-drying or irritation to the skin. A blinded, controlled study should be conducted to normalize any effect from the use of Camay.27

Third, ingestion of BCC was accompanied by increased collagen content in the dermis. Unlike other efficacy parameters, however, its increase was significant at week 6, but not at week 12. It was not clear why the effect of BCC dampened as the study progressed. Seasonal or dietary factors may have been involved. A controlled study including more subjects is needed to verify the effects of BCC not only on collagen content but also on the content of diverse skin molecules and facial aging signs.

Despite its limited effect on collagen content, BCC supplementation appeared to affect metabolic balance between biosynthesis of collagen type I and/or type III by dermal fibroblasts and their degradation by MMPs. This is intriguing because collagen present in BCC is predominantly type II, as it is extracted from chicken sternal cartilage which belongs to articular or hyaline cartilage. One of the major constituents of BCC is hydrolyzed collagen type II. Interestingly, both hydrolyzed collagen type II derived from chicken sternal cartilage, and hydrolyzed collagen type I derived from bovine skin, stimulate chondrocytes to produce collagen type II in vitro,11 which was likely due to a high level of homology in their amino acid sequences. Additionally, the Pro-Hyp dipeptide, a major peptide form present in the human blood following the ingestion of either the hydrolyzed chicken cartilage extract or hydrolyzed collagen derived from bovine skin, was shown to stimulate human dermal fibroblasts to produce HA in vitro.12,28 It remains unknown whether the dipeptide or other biologically active compounds derived from hydrolyzed chicken cartilage extract can directly stimulate dermal fibroblasts for de novo biosynthesis of collagen type I, which is most abundant in the skin dermis.

This study provided preliminary evidence that ingestion of BCC, a hydrolyzed chicken sternal cartilage extract, affects aging-associated physiological processes and reduces visible aging signs in the face. A controlled, long-term human study as well as in vitro studies is necessary to verify the antiaging effect of BCC supplement and to better understand its potential mechanisms.

This web site is neither for advertising nor dispensing of medical advice. Clients who consult with Dr. Weeks receive information in an educational context in an effort to learn about optimizing care with their local health care practitioners. Dr. Weeks formerly practiced on Whidbey Island off the coast of Washington.

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